Obesity is a major risk factor for type 2 diabetes, which in turn has serious complications including accelerated development of cardiovascular disease. The prevalence of obesity in children and adults in the United States has increased by more than 30% over the past decade. We previously successfully argued in our application for the R01 HD056465 award that distillation of the genetic component in this complex phenotype should thus be easier to determine in children, where environmental exposure and impact has been for a relatively short period of their lifetime; indeed the resulting work did pan out to be successful in this regard. We carried out a non-hypothesis-driven study that was directed at uncovering genes and genetic variants that predispose to childhood obesity by conducting a genome-wide association study (GWAS) using a high density tag-SNP array. Employing a powered two-stage study design in a consortium setting, where cases were defined as being in the e95th percentile of BMI, we identified novel association signals which we subsequently replicated. This NICHD funded study was ultimately published in Nature Genetics (with the PI as senior author) and received widespread press attention, including with CNN, Time and the front page of USA Today. The Children's Hospital of Philadelphia is now poised to determine additional genetic factors conferring risk to the pathogenesis of childhood obesity through the leveraging of new ultra-high-throughput sequencing technology, and also allow for fine-mapping of the already uncovered loci to determine the actual causal mechanism of action. Combining our accurately phenotyped cohort, which represents the largest pediatric obesity DNA collection in the world, with access to familial childhood obesity, availability of existing genome wide singl nucleotide polymorphism genotypes and the application of whole exome sequencing, this renewal application of R01 HD056465 proposes to broaden the list of novel genetic loci that are associated with this trait in order to get further insights in to the genetic etiology of common pediatric obesity. We are well positioned to extend our knowledge of the genetic etiology of childhood obesity. It is unclear if these additional variants are common in the population, a set o private mutations in families or a mixture of both. Irrespective of the nature of the variant(s) we are well positioned to look for both types of event, with common variants detectable through leveraging the GWAS dataset of well powered cohorts and private mutations detectable through whole exome sequencing of many multi-case pedigrees. This represents a major follow-up to the Principal Investigator's original grant application and this renewal will allow for adding extr value to the already substantial findings made funded by the original grant.